NSF-BSF: Synchronous electro-optical DNA detection using low-noise dielectric nanopores on sapphire

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Nanopore DNA sensing is an emerging technology, and has recently been developed to detect both the DNA primary sequence and epi-genetic information (such as methylation), which is crucial to both fundamental biology and precision medicine.. However, high-speed and accurate DNA methylation detection in nanopores still lags behind. This is attributed to an insufficient signal-to-noise ratio (SNR) resulting from the inherent large electrical capacitive noise from the conductive silicon (Si) and also the complex DNA dynamic interaction with nanopore surface. This project proposes a multidisciplinary research plan to address the fundamental challenges in high-speed and low-noise biomolecular sensing in a solid-state nanopore device. The new design combines electrical and optical sensing on a single sensor platform to improve the sensing accuracy. It utilizes crystalline sapphire as an insulating substrate and integrates large-bandgap titanium oxide thin film as the sensing element to minimize both the electronic and optical noise. The demonstration of DNA methylation detection will prove the feasibility of our TiO2/sapphire nanopore sensors in detecting complex molecular structures that will have broad impact on molecular marker detection and molecule-molecule interactions. The educational objectives are to promote electronic nanosensors related engineering education to undergraduate and graduate students, and to better prepare them as future innovators to transform nanobiotechnologies. The outreach objectives are to promote public awareness of the importance of nanosensors in health care and to attract the participation of K-12 students and underrepresented individuals in STEM careers.This research is to fill the knowledge gap in nanopore sensing research by creating a significantly improved nanopore sensor platform that integrates low-optical background titanium oxide membranes on low-capacitance and hence low-electrical-noise sapphire. The research team will fabricate small and thin TiO2 membranes on sapphire, establish high-throughput manufacturing methods for both membrane formation and nanopore drilling, perform single-molecule DNA translocation, study the DNA-nanopore interaction, and analyze the data for methylation detection. The proposed sensor platform has a number of key features to support the development of a wide variety of emerging biomolecular diagnostic technologies. First, the creation of ultrasmall (10 μm) dielectric membranes on insulating sapphire eliminates substrate conductance, and drastically minimizes the chip capacitance to a few picoFarads even for high-dielectric-constant and ultrathin (5 nm) TiO2 devices, thus significantly reducing the background high-frequency electrical noise and markedly improving high-bandwidth sensing. Further, both membrane formation and nanopore drilling will be achieved by high-throughput manufacturing methods, i.e. wafer-scale and batch-processing compatible sapphire etching and direct laser drilling, thus enabling low-cost and repeatable production. The scalably manufactured, low-noise, high-sensitivity nanopores will facilitate high-resolution gene identification and quantitation of their methylation status in a single measurement and at a greatly reduced cost.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.